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19th Ave New York, NY 95822, USA

Del Valle, Juan

Juan Del Valle

University of Notre Dame

Talk Session: SESSION 14: STRUCTURAL METHODS IN PEPTIDE SCIENCE
Date: Thursday, June 16, 2022
Talk Time: 11:10 am - 11:30 am
Talk Title: Beyond N-Methylation: Synthesis, Structure, and Function of N-Heteroatom-Substituted Peptides

2019-present William K. Warren Family Associate Professor, University of Notre Dame; 2015-2019 Associate Professor, University of South Florida; 2009-2015 Assistant Professor, University of South Florida and Moffitt Cancer Center; 2006-2008 Assistant Professor, New Mexico State University; 2004-2006 Postdoctoral Scholar, University of Montreal; 2004 Ph.D. in Chemistry, University of California San Diego; 1999 BA in Chemistry, Carleton College

The Del Valle lab is broadly interested in bringing the power of organic chemistry to bear on current challenges in drug discovery and biomolecular recognition. Our research program lies at the interface of organic synthesis and chemical biology, with an emphasis on the structure-based design of biologically active peptidomimetics and small molecules. We view non-canonical peptides and stabilized protein folds as the ‘next wave’ in drug discovery, and we are working to realize their promise as potential therapeutics.

Despite the importance of well-defined protein-protein interactions, PPIs, in promoting various diseases, the development of molecules capable of modulating these interactions remains a significant challenge. This situation stems from a chemical biology paradox in which the need to bind large protein surfaces with precise topology is beset by the flexibility and cell-impermeability of high molecular weight inhibitors. Our lab is targeting a number of PPIs using designed protein mimics. Efforts in this area include disruption of neurodegenerative protein aggregation as well as PPIs that drive cancer and autoimmune disorders.

Nature remains a prolific source of drug candidates, with almost half of all FDA-approved therapeutics classified as natural product derived or inspired. Non-ribosomal peptides, NRPs, represent a particularly promising class of natural products with diverse biological activities. NRPs are predisposed to interact with protein receptors and often feature drug-like properties not typically seen in canonical polypeptides. We are pursuing the synthesis of NRPs in which unusual amino acids or unique backbone modifications are important for biological activity. We also leverage synthetic access to these residues in order to study their effects on native peptide/protein conformation and their utility in other drug design applications.

Endoplasmic reticulum, ER, stress resulting from gene amplification and aberrant protein expression is an established hallmark of cancer. As a result, many tumors hijack ER stress response mechanisms in order to evade cell death. As part of a highly collaborative effort with immunologists, cell biologists, and clinicians, our lab has developed a series of potent inhibitors of the IRE1/XBP1 signaling arm of the ER stress response. These compounds have helped to establish the clinical relevance of targeting IRE1 in a variety of disease models including chronic lymphocytic leukemia, c-Myc-driven cancers, and graft-versus-host disease. Current efforts are aimed at chemical optimization, advanced pre-clinical development, and elucidating the role of ER stress response in other diseases using new chemical probes.

Backbone-oxidized non-ribosomal peptidem, NRP, natural products have garnered considerable interest due to their unique conformational preferences and intriguing biological activities. Inspired by these NRPs, our laboratory is exploring the synthesis and properties of designed N-heteroatom-substituted peptides and proteins. We have examined the impact of hydrazide and hydroxamate backbone replacements on the stability of canonical secondary structures using NMR, X-ray, and circular dichroism.

Here, we demonstrate how cooperative non-covalent interactions contribute to help accommodate hydrazide bonds within b-strand, polyproline II, and a-helical folds. In particular, peptide N-amination is shown to stabilize &beat;-sheets while enhancing peptide solubility and proteolytic stability, thus addressing a significant challenge in the area of protein mimicry.

The conformational and non-aggregating characteristics of N-amino peptides, NAPs, are consistent across distinct models of folding in aqueous solution and in the solid-state. Leveraging these properties, we designed a series of linear and macrocyclic NAPs that target protein fibrilization and block the propagation of amyloid assemblies in a sequence-specific manner.

We further show that backbone N-amino substituents within peptides can serve as reactive handles in late-stage macrocyclizations. This enables the incorporation of novel covalent surrogates of sidechain-to-backbone, sb, H-bonds that are prevalent motifs in globular proteins. N-Heteroatom-substituted peptides thus represent nature-inspired tools for protein mimicry with broad ranging applications in chemical biology and peptidomimetic drug design.

Juan Del Valle